1-33334206-C-T

Position:

• chr1-33334206-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001385109.1(PHC2):​c.1645G>A​(p.Ala549Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,612,788 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (38 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (30 hom.)
• Consequence: PHC2 NM_001385109.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0530

Genes affected

PHC2 (HGNC:3183): (polyhomeotic homolog 2) In Drosophila melanogaster, the 'Polycomb' group (PcG) of genes are part of a cellular memory system that is responsible for the stable inheritance of gene activity. PcG proteins form a large multimeric, chromatin-associated protein complex. The protein encoded by this gene has homology to the Drosophila PcG protein 'polyhomeotic' (Ph) and is known to heterodimerize with EDR1 and colocalize with BMI1 in interphase nuclei of human cells. The specific function in human cells has not yet been determined. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

PHC2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017902851).
• BP6: Variant 1-33334206-C-T is Benign according to our data. Variant chr1-33334206-C-T is described in ClinVar as [Benign]. Clinvar id is 770113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0116 (1767/152174) while in subpopulation AFR AF= 0.0406 (1685/41510). AF 95% confidence interval is 0.039. There are 38 homozygotes in gnomad4. There are 826 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 38 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHC2	NM_001385109.1	c.1645G>A	p.Ala549Thr	missense_variant	10/15	ENST00000683057.1	NP_001372038.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHC2	ENST00000683057.1	c.1645G>A	p.Ala549Thr	missense_variant	10/15		NM_001385109.1	ENSP00000507877.1

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1756 AN: 152056 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.0404

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00309 AC: 773 AN: 249948 Hom.: 10 AF XY: 0.00226 AC XY: 306 AN XY: 135200

Gnomad AFR exome AF: 0.0416

Gnomad AMR exome AF: 0.00218

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000550

Gnomad SAS exome AF: 0.0000984

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000985

GnomAD4 exome AF: 0.00115 AC: 1683 AN: 1460614 Hom.: 30 Cov.: 32 AF XY: 0.00100 AC XY: 728 AN XY: 726690

Gnomad4 AFR exome AF: 0.0397

Gnomad4 AMR exome AF: 0.00260

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000459

Gnomad4 OTH exome AF: 0.00275

GnomAD4 genome AF: 0.0116 AC: 1767 AN: 152174 Hom.: 38 Cov.: 32 AF XY: 0.0111 AC XY: 826 AN XY: 74406

Gnomad4 AFR AF: 0.0406

Gnomad4 AMR AF: 0.00321

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00495 Hom.: 4

Bravo AF: 0.0135

ESP6500AA AF: 0.0386 AC: 170

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00406 AC: 493

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 19, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.0096	T;.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.73	T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.26	.;.;.;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.31	.;N;N;N
REVEL	Benign	0.16
Sift	Benign	1.0	.;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0010	.;.;.;B
Vest4		0.091
MVP		0.17
MPC		0.45
ClinPred		0.0028	T
GERP RS		-3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.061
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs115905637; hg19: chr1-33799807;